Identification of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir

• Published in: bioRxiv
• Main Authors: Krismer, Laura, Schoeppe, Helge, Rauch, Stefanie, Bante, David, Sprenger, Bernhard, Naschberger, Andreas, Costacurta, Francesco, Fuerst, Anna, Sauerwein, Anna, Rupp, Bernhard, Kaserer, Teresa, Dorothee Von Laer, Heilmann, Emmanuel
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.12.2023
• Subjects: Antiviral agents; Coronaviruses; COVID-19; Disease resistance; Drug development; Middle East respiratory syndrome; Mutagenesis; Pandemics; Pathogens; Proteinase inhibitors; Respiratory diseases; Severe acute respiratory syndrome coronavirus 2
• DOI: 10.1101/2023.12.04.569917

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35 % and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of the SARS-CoV-2 and MERS-CoV main proteases. Furthermore, we selected MERS-CoV-Mpro mutants resistant against nirmatrelvir, the most effective inhibitor of this protease, with a safe, surrogate virus-based system, and suggest putative resistance mechanisms. Notably, nirmatrelvir demonstrated effectiveness against various viral proteases, illustrating its potential as a broad-spectrum coronavirus inhibitor. To adress the inherent resistance of MERS-CoV-Mpro to ensitrelvir, we applied directed mutagenesis to a key ensitrelvir-interacting residue and provided structural models.Competing Interest StatementD.v.L. is founder of ViraTherapeutics GmbH. D.v.L serves as a scientific advisor to Boehringer Ingelheim and Pharma KG. E.H. and D.v.L have received an Austrian Science Fund (FWF) grant in the special call 'SARS urgent funding'. D. Bante holds stocks of Pfizer Inc. and Oxford Nanopore Technologies plc. All other authors declare no competing interest.